Our long-term goal is to develop novel therapeutic agents targeted to slowing the development of t neurofibrillary pathology in Alzheimer's disease (AD) by preserving the integrity of the cytoskeleton. Based on the pronounced neuronal dystrophy and disruption of microtubule (MT) integrity observed in AD brain and neurons exposed to Ab fibrils, we have tested the effects of MT-stabilizing drugs such as Taxol for protection against Ab toxicity. Taxol and several other MT-stabilizing drugs markedly enhanced survival of Ab-treated neurons in culture. However, these drugs do not enter the brain and thus cannot be tested in an in vivo mouse model for AD. We have synthesized two novel compounds that protect neurons in culture and actually cross the blood brain barrier (BBB). Pharmacokinetic studies on the half-lives and the brain distribution of the drugs have already been completed, as have limited toxicity experiments. The goal of this project is to use a recently developed triple transgenic mouse model (3xTg-AD) with both Ab and t pathology to conduct an in vivo proof-of concept study. The Specific Aims are: (1) to determine the maximal tolerated doses of the two drugs in control mice receiving chronic administration for several weeks; (2) to test the in vivo effects of the brain permeant taxane Tx-67 and the non-taxane MT-interacting drug GS-164 in the 3xTg-AD mouse model by assessing the behavioral performance of the mice throughout the period of chronic drug administration; and (3) to evaluate the in vivo effects of chronic treatment with Tx-67 or GS-164 on the progression of the AD-like neuropathological lesions that develop in the 3xTg-AD mic. Drug-treated mice will be compared with control animals receiving only saline injections. Behavioral testing will be done bi-weekly throughout the treatment period. Brains will be analyzed for indicators of both amyloid and t lesions using standard neuropathological, immuno-histochemical, and biochemical strategies. Based on our in vitro studies with primary neurons in culture and a recent report that Taxol reversed peripheral axonal transport deficits in spinal cord neurons of a tauopathy mouse, we anticipate the drugs will moderate the brain pathology in the 3xTg-AD mice. The drugs we have identified make it possible for us to provide the very first in vivo evaluation of brain permeant MT-stabilizing drugs for their potential to slow the progression of AD-like neuropathology in the brain. If the drugs do indeed alter the progression of any cognitive changes and/or the accumulation of the brain lesions, the findings would support further investigation into this very novel therapeutic strategy for slowing age-dependent neurodegeneration such as occurs in AD. [unreadable] [unreadable]